Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/58—Materials at least partially resorbable by the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

• the present invention is directed to semi-crystalline absorbable microspheres that may be used as fillers, a method for making such microspheres and formulations comprising such absorbable microspheres.
• Fillers can be used in soft tissue augmentation to aesthetically reduce the effects of aging and other soft tissue defects.
• a filler that is to be used intradermally to be absorbable and soft to the touch.
• the filler should not be palpable under the skin either initially upon application or over time.
• Absorbable polymers that are known to be soft to the touch are those having low glass transition temperatures, including but not limited to ⁇ -caprolactone and p -dioxanone, and copolymers thereof.
• a filler is ideally easy to use and produces reproducible and long-lasting results.
• the filler may be comprised of microspheres that can pass through a small needle for injection subcutaneously or intradermally, without aggregating or agglomerating under pressure, thereby avoiding clogging of a delivery device such as a needle.
• microspheres it is desirable for the microspheres to retain their distinct spherical shape without aggregating or agglomerating (hereinafter referred to as "dimensional stability"), upon manufacture, storage and physical transport.
• dimensional stability aggregating or agglomerating
• USP 6,716,251 describes absorbable microspheres or microparticles suspended in a gel, where the microspheres or microparticles may be polycaprolactones, polylactides, polyglycolides and their copolymers.
• the microspheres or microparticles may be polycaprolactones, polylactides, polyglycolides and their copolymers.
• copolymers of polycaprolactones, polylactides, and polyglycolides preferred polymers are poly-L-lactic acid, poly-D-lactic acid, or a mixture thereof, having a molecular mass ranging from between 70,000 and 175,000 Dalton, and preferably between 120,000 and 170,000 Dalton.
• absorbable copolymers of ⁇ -caprolactone or p -dioxanone that are semicrystalline in nature, to make microspheres that may be used, for example, in plastic surgery applications and that retain their distinct spherical shape upon manufacture, storage, and physical transportation.
• the present invention is directed to absorbable microspheres comprising a copolymer formed from greater than 88 to about 99 mole percent ⁇ -caprolactone or p -dioxanone, and about 1 to less than 12 mole percent of a different second monomer selected from the group consisting of glycolide, p -dioxanone, trimethylene carbonate and the lactides (L-lactide, D-lactide and meso -lactide) and combinations thereof, said microspheres having a particle size ranging from about 5 to 2,000 microns. Also described herein are a method for making such microspheres and formulations comprising such absorbable microspheres.
• Described herein are copolymers of ⁇ -caprolactone or p -dioxanone, and at least a different second monomer selected from the group consisting of glycolide, p- dioxanone, trimethylene carbonate and the lactides, that are absorbable within 6 to 24 months and that may be used to make microspheres having a particle size ranging from about 5 to 2,000 microns, and preferably from about 30 to 75 microns.
• the microspheres described herein are capable of retaining their distinct spherical shape during manufacture, storage, and physical transportation.
• the amount of ⁇ -caprolactone or p -dioxanone present in the copolymer described herein ranges from greater than 88 to about 99 mol %, and preferably from about 90 to 97%.
• the amount of the different second monomer ranges from about 1 to less than 12 mol%, and preferably from about 3 to 10 mol%.
• the copolymer described herein may contain the second monomer in an amount as low as 0.5 to 0.99 mol%, for example, when a ⁇ -caprolactone is polymerized in the presence of a glycolic acid initiator at a ratio of monomer: initiator of 30:1 to 100:1, yielding a polycaprolatone polymer chain having glycolic acid residues incorporated therein.
• the total residual monomer (defined as the total amount of unreacted monomer present in the copolymer) in the copolymer is no greater than about 0.5 weight percent of the microspheres.
• the copolymer is a semi-crystalline material, having a degree of crystallinity ranging from about 10 to less than 65%, and preferably from about 30 to 45%.
• the copolymer may be a randomized copolymer, a block copolymer or a segmented block copolymer, having a molecular weight ranging from about 1,000 to about 50,000 daltons, preferably from about 5,000 to 30,000 daltons, and most preferably from about 15,000 to 23,000 daltons.
• microspheres described herein may be made by coacervation, for example as described in USP 5,000,886 , solvent evaporation, and droplet extrusion with a spinning disk.
• Other methods of manufacture that may be utilized for formation of microspheres include but are not limited to spray coating, pan-coating, spray-drying, phase separation, emulsion polymerization, and interfacial polymerization.
• the absorbable microspheres described herein may be prepared from a copolymer formed from about 90 to 97 mole percent ⁇ -caprolactone and about 3 to 10 mole percent of glycolide, said copolymer having a molecular weight of between about 15,000 to 23,000 Daltons, by (a) forming an emulsion of the copolymer, a solvent such as methylene chloride, chloroform, trichloroethylene, and similar solvents with solubility parameters in the range of those described herein ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide and a non-solvent, for example silicone oils such as polydimethylsiloxane, cyclic polydimethylsiloxanes, mineral oils, vegetable oils, wherein the copolymer-solvent forms a microspherical phase and the non-solvent polydimethylsiloxane forms a continuous phase; (b) extracting the micros
• the microspheres described herein may be incorporated into a formulation that is suitable for delivery into the human body via, for example, a syringe.
• the formulation may comprise the microspheres suspended in a suspending medium such as a gel.
• the formulation may comprise the microspheres, water and a gelling agent approved for use in injections, such as cellulose derivatives, including but not limited to carboxymethylcellulose (CMC), at a concentration by mass ranging from about 0.1 to 7.5%, and preferably from about 0.1 to 5.0%, or hyaluronic acid at a concentration of up to 2% by weight.
• Additional gelling agents include but are not limited to hydroxypropyl-methylcellulose (HPMC), which is commonly used in intraocular injection during cataract operations; lactic acid esters, caproic acid esters and the like.
• the formulation may comprise a surfactant, including but not limited to polyoxyethylene sorbitan monooleate (marketed under the brandname Tween 80), Span 20 or pluronic acid, in order to improve the homogeneity of the formulation or gel.
• a surfactant including but not limited to polyoxyethylene sorbitan monooleate (marketed under the brandname Tween 80), Span 20 or pluronic acid, in order to improve the homogeneity of the formulation or gel.
• the formulation may be packaged in ready-for-use pre-filled sterile syringes, or in vials.
• the formulation may be packaged in a vial as freeze-dried product accompanied by a separate ampuole of sterile fluid (i.e., water for injection) that may be combined prior to use; or in a two-compartment pre-filled syringe, one containing the freeze-dried formulation, the other containing water, saline or intravenous solutions or other organic carriers.
• sterile fluid i.e., water for injection
• the molten polymer is dropped from the reactor and collected as polymer blocks. After cooling to room temperature, the polymer is further cooled under liquid nitrogen, before it is ground into powder with a polymer grinder.
• the molar composition of the polymer by 1 H NMR analysis is: Polycaprolactone 93.6% PGA 6.2% Glycolide 0.0% ⁇ -caprolactone 0.3%
• the inherent viscosity in hexafluoroisopropanol at a solution concentration of 0.1 g/dL is 0.38 dUg.
• the weight average molecular weight (Mw) is 7,540 Daltons.
• Microspheres are formed in a 2-liter resin flask provided with stirrer, nitrogen inlet, condenser and cold trap by the following solvent evaporation process.
• the flask is charged with 1,650 grams of a 3% w/w polyvinyl alcohol water solution. Stirrer rotation is set at about 246 RPM.
• a 7.5% w/w solution of the 94/6 ⁇ -caprolactone / glycolide copolymer (cap/gly copolymer) in methylene chloride (277.8 grams of solution) is substantially uniformly added over a period of about 13 minutes into the side of the vortex, forming an oil in water emulsion.
• Methylene choride is evaporated by passing nitrogen over the surface of the stirred solution for about 14 hours. The agitation is stopped and the formed microspheres are allowed to settle at the bottom of the flask and the supernatant liquid is removed. The microspheres are repeatedly washed with deionized water, allowing time for settling of the microspheres at the bottom of the flask before removing the supernatant liquid. The microspheres are wet-screened from the water slurry using two stacked stainless steel screens (screen sizes 38 microns and 75 microns), and collecting the fraction between 38 and 75 microns. The microspheres are then vacuum dried at room temperature until removal of water is accomplished. A total of 14.8 grams of microspheres is collected, giving a yield of 71 %.
• microspheres showed a crystallinity of 38.7%as measured by x-ray diffraction and Scanning Electron Microscopy (SEM) pictures showed microspheres having distinct spherical shape.
• the microspheres are sterilized in closed vials by gamma radiation at 25 kGy and are easily re-dispersed in sterile sodium carboxymethylcellulose, water solutions, or saline water solutions, as well as in a sodium hyaluronate water, or saline water solutions, having viscosities in the range of about 5 to about 50 centipoises.
• the molten polymer is dropped from the reactor and collected as polymer blocks. After cooling to room temperature, the polymer is further cooled under liquid nitrogen, before it is ground into powder with a polymer grinder.
• the molar composition of the polymer by 1 H NMR analysis is: polycaprolactone 96.9% PGA 3.1 % glycolide 0.0% ⁇ -caprolactone 0.0%
• the weight average molecular weight (Mw) is 15,100 Daltons.
• Microspheres are formed in a 2- liter resin flask provided with stirrer, nitrogen inlet, condenser and cold trap by the following solvent evaporation process:
• the flask is charged with 1,412 grams of a 3% w/w polyvinyl alcohol water solution. Stirrer rotation is set at about 246 RPM .
• a 7.5% w/w solution of the 97/3 cap/gly polymer in methylene chloride (231.2 grams of solution) is substantially uniformly added over a period of about 16 minutes into the side of the vortex, forming an oil in water emulsion.
• Methylene choride is evaporated by passing nitrogen over the stirred surface of the solution for about 14 hours.
• microspheres are allowed to settle at the bottom of the flask and the supernatant liquid is removed.
• the microspheres are repeatedly washed with deionized water allowing time for settling of the microspheres at the bottom of the flask before removing the supernatant liquid.
• the microspheres are wet-screened from the water slurry using two stacked stainless steel screens (screen sizes 38 microns and 75 microns) and the fraction between 38 and 75 microns is collected. The microspheres are then vacuum dried at room temperature until removal of water is accomplished.
• the microspheres show a crystallinity of 40.1 %.
• the microspheres are sterilized in closed vials by gamma radiation at 25 kGy, at a dose rate of 14.32 kGy/hr. and are easily re-dispersed in sterile sodium carboxymethylcellulose, water solutions, or saline water solutions, as well as in a sodium hyaluronate water, or saline water solutions having viscosities in the range of about 5 to about 50 centipoises.
• the polymer After cooling to room temperature, the polymer is further cooled under liquid nitrogen, before it is ground into powder with a polymer grinder.
• the molar composition of the polymer by 1 H NMR analysis is: polycaprolactone 98.7% PGA 1.3% ⁇ -caprolactone 0. %
• the weight average molecular weight is 6,600 Daltons.
• Microspheres are formed in a 2 liter resin flask provided with stirrer, nitrogen inlet, condenser and cold trap by the following solvent evaporation process:
• the flask is charged with 1,500 grams of a 3% w/w polyvinyl alcohol water solution. Stirrer rotation is set at about 240 RPM.
• a 7.5% w/w solution of the glycolic acid initiated polycaprolactone polymer in methylene chloride (270 grams of solution) is substantially uniformly added over a period of about 19 minutes into the side of the vortex, forming an oil in water emulsion.
• Methylene choride is evaporated by passing nitrogen over the surface of the solution for about 16 hours.
• microspheres are allowed to settle at the bottom of the flask and the supernatant liquid is removed.
• the microspheres are repeatedly washed with deionized water, allowing time for settling of the microspheres at the bottom of the flask before removing the supernatant liquid.
• the microspheres are wet- screened from the water slurry using two stacked stainless steel screens (screen sizes 38 microns and 75 microns), and collecting the fraction between 38 and 75 microns.
• the microspheres are then vacuum dried at room temperature until removal of water is accomplished, and subsequently are dried at 40°C for 16 hours. A total of 7.28 grams of microspheres is collected.
• microspheres are sterilized in closed vials by gamma radiation at 25 kGy and are easily re-dispersed in sterile sodium carboxymethylcellulose, water solutions, or saline water solutions, as well as in a sodium hyaluronate water, or saline water solutions, having viscosities in the range of about 5 to about 50 centipoises.
• the polymer After cooling to room temperature, the polymer is further cooled under liquid nitrogen, before it is ground into powder with a polymer grinder.
• the molar composition of the polymer by 1 H NMR analysis is: polycaprolactone 99.4% PGA 0.5% ⁇ -caprolactone 0.1 %
• the weight average molecular weight is 20,200 Daltons.
• Microspheres are formed in a 2-liter resin flask provided with stirrer, nitrogen inlet, condenser and cold trap by the following solvent evaporation process:
• the flask is charged with 1,500 grams of a 3% w/w polyvinyl alcohol water solution. Stirrer rotation is set at about 240 RPM.
• a 7.5% w/w solution of the glycolic acid initiated polycaprolactone polymer in methylene chloride (270 grams of solution) is substantially uniformly added over a period of about 12 minutes into the side of the vortex, forming an oil in water emulsion.
• Methylene choride is evaporated by passing nitrogen over the surface of the solution for about 16 hours.
• microspheres are allowed to settle at the bottom of the flask and the supernatant liquid is removed.
• the microspheres are repeatedly washed with deionized water, allowing time for settling of the microspheres at the bottom of the flask before removing the supernatant liquid.
• the microspheres are wet- screened from the water slurry using two stacked stainless steel screens (screen sizes 38 microns and 75 microns) and collecting the fraction between 38 and 75 microns .
• the microspheres are then vacuum dried at room temperature until removal of water is accomplished, and subsequently are dried at 40°C for 16 hours. A total of 7.28 grams of microspheres is collected.
• microspheres are sterilized in closed vials by gamma radiation at 25 kGy and are easily re-dispersed in sterile sodium carboxymethylcellulose, water solutions, or saline water solutions, as well as in a sodium hyaluronate water, or saline water solutions, having viscosities in the range of about 5 to about 50 centipoises.
• the molar composition of the polymer by 1 H NMR analysis is: polycaprolactone 87.5% PGA 12.4% ⁇ -caprolactone 0.1 %
• the weight average molecular weight is 10,300Daltons
• Microspheres are formed in a 2-liter resin flask provided with stirrer, nitrogen inlet, condenser and cold trap by the following solvent evaporation process:
• the flask is charged with 1,625 grams of a 3% w/w polyvinyl alcohol water solution. Stirrer rotation is set at about 241 RPM .
• a 7.5% w/w solution of the 88/12 cap/gly copolymer in methylene chloride (269.1 grams of solution) is substantially uniformly added over a period of about 15 minutes into the side of the vortex, forming an oil in water emulsion.
• Methylene choride is evaporated by passing nitrogen over the surface of the solution for about 16 hours.
• microspheres are allowed to settle at the bottom of the flask and the supernatant liquid is removed.
• the microspheres are repeatedly washed with deionized water, allowing time for settling of the microspheres at the bottom of the flask before removing the supernatant liquid.
• the microspheres are wet- screened from the water slurry using two stacked stainless steel screens (screen sizes 38 microns and 75 microns) and collecting the fraction between 38 and 75 microns.
• the microspheres are then vacuum dried at room temperature until removal of water is accomplished, and subsequently are dried at 40°C for 16 hours.
• the microspheres were examined by SEM under high vacuum, which formation of some agglomerates after wet screening and drying, are not seen at compositional ranges of higher ⁇ -caprolactone content.
• the molar composition of the polymer by 1 H NMR analysis is: polycaprolactone 84.6% PGA 14.5% ⁇ -caprolactone 0.9 %
• the molten polymer is dropped from the reactor and collected as polymer blocks. After cooling to room temperature, the polymer is further cooled under liquid nitrogen, before it is ground into powder with a polymer grinder.
• the molar composition of the polymer by 1 H NMR analysis is: polycaprolactone 93.9% PGA 5.5% glycolide 0.% ⁇ -caprolactone 0.6%
• the inherent viscosity in hexafluoroisopropanol at a solution concentration of 0.1 g/dL is 0.73 dUg.
• the weight average molecular weight is 18,900Daltons.
• a 200mL cylindrical glass container Into a 200mL cylindrical glass container is charged 62.5 grams of a 4.0 % w/w solution of 94/6 s-caprolactone / glycolide copolymer copolymer in methylene chloride. 250 grams of polydimethylsiloxane (360 Medical Fluid, 350 CST, commercially available from Dow Corning) is slowly added to the polymer solution under stirring to form 312.5 grams of emulsion. The polymer solution is broken down into droplets by agitation and dispersed in the polydimethylsiloxane continuous phase to form microspheres. The emulsion is continuously agitated for about 150 minutes.
• polydimethylsiloxane 360 Medical Fluid, 350 CST, commercially available from Dow Corning
• the emulsion was transferred to another glass container containing approximately 3,125 grams of decamethylcyclopentasiloxane (PENTAMERE SILBIONE® D5, commercial available from Rhodia) at a controlled temperature of about 6 °C with stirring to harden the microspheres.
• the mixture is kept at a temperature of 6 °C with stirring for approximately 120 minutes to achieve full solvent extraction and hardening of the polymeric microspheres.
• the microspheres are recovered by filtration utilizing a 10 micron stainless steel screen filter. The microspheres are washed on the filter with fresh decamethylcyclopentasiloxane, and they are dried under vacuum.
• Microspheres from the 94/6 ⁇ -caprolactone / glycolide copolymer of Example 7 are made by the coacervation method under different conditions.
• Into a 200mL cylindrical glass container is charged 120 grams of a 2.5% w/w solution of 94/6 ⁇ -caprolactone / glycolide copolymer in methylene chloride.
• Polydimethylsiloxane 270 grams (360 Medical Fluid, 350 CST, commercially available from Dow Corning), is slowly added to the polymer solution under stirring to form 390 grams of emulsion.
• the polymer solution is broken down into droplets by agitation and dispersed in the polydimethylsiloxane continuous phase to form microspheres.
• the emulsion is continuously agitated for about 120 minutes.
• the emulsion was transferred to another glass container containing approximately 3,108 grams of decamethylcyclopentasiloxane (PENTAMERE SILBIONE® D5, commercial available from Rhodia) at a room temperature of 24 °C to harden the microspheres with stirring. A couple of minutes after the emulation is transferred, the aggregation of the microspheres occurs.
• PENTAMERE SILBIONE® D5 decamethylcyclopentasiloxane

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